Infection of the central nervous system with HIV-1 can trigger a cascade of defense mechanisms that are aimed at blocking expression of the viral genome at various stages of its life cycle. In turn, HIV-1 has evolved several regulatory events via its accessory proteins, more notably Tat, to overcome the cellular defense pathways and through a series of diverse modulatory event induces maximum damage to the cells while ensuring a productive viral life cycle in the infected cells. Recently, much attention has been focused on the impact of HIV-1 infection on host cell homeostasis, more specifically the interaction of HIV-1 with cellular pathways that control chromosomal integrity via homologous and non-homologous DNA repair. While the role of HIV-1 Vpr in affecting DNA damage is well documented, recent observations (shown here) point to the ability of Tat in the induction of Rad51 expression in primary microglia and astrocytes, the two cell types that play an important role in neuropathogenesis of AIDS. This observation corroborates the results from infection studies showing increased levels of Rad51 in HIV-1 infected microglia and astrocytes in culture and in AIDS brain with HIV encephalitis. Rad51 is the major regulator of the homologous recombination repair pathway that in coordination with other cellular proteins ensures chromosomal integrity. Evidently, unscheduled activation of Rad51 may have an adverse impact on several cellular pathways and in some instances even compromise chromosomal integrity. Interestingly, induction of Rad51 by Tat protein may have a positive feedback effect on HIV-1 promoter activity in microglia and astrocytes. In this respect, our preliminary data point to the possible recruitment of NF-B and cyclin T1, the two regulators of HIV-1, by Rad51 for stimulation of the LTR in CNS cells. All these observations provide a rationale for us to hypothesize that the reciprocal interaction of HIV-1 through its transactivator, Tat, with the host recombination repair regulator, Rad51 creates a condition that leads to activation of the HIV-1 promoter in microglia, astrocytes and possibly macrophages, and alters host recombination repair pathways in favor of HIV-1. In this application, we seek support to launch a series of well-integrated molecular, virological, and cellular studies to decipher the molecular events associated with cross-communication of HIV-1 and host DNA repair machinery and develop a strategy, based on our observations, to inhibit HIV-1 gene expression and activation in cells that support viral infection. Throughout our studies the relevance of our molecular discoveries to the neuropathogenesis of HIV-1 will be verified at every stage through the use of a unique collection of brain specimens from HIVE patients (provided by the Manhattan Brain Bank). Thus, through this novel integrated approach, our studies will provide important information relevant to HIV-1/CNS diseases that can be used to improve the current method for treatment of AIDS patients with neurological disorders.